Here we examine the molecular mechanisms regulating synovial tissue architecture and function. The[unreadable] synovial lining demonstrates cellular compaction of fibroblast-like synoviocytes (FLS) and macrophages[unreadable] within an ordered extracellular matrix. In inflammatory arthritis, this lining exhibits marked hyperplasia and[unreadable] pannus formation and functionally acquires the ability to migrate over, attach to, and erode into adjacent[unreadable] cartilage and bone. The major mesenchymal cells of the synovial lining, the FLS, are thought to be[unreadable] intimately involved in regulating the physiology and architecture of the normal synovial membrane and of[unreadable] the abnormal synovium in inflammatory arthritis. We found that the cadherin family of proteins, specifically[unreadable] cadherin-11, is expressed on FLS and is a major factor in their cellular adhesion, migration and invasion[unreadable] and in formation of the synovial lining. Strikingly, in cadherin-11 deficient mice, the synovial lining is[unreadable] hypoplastic at baseline and further, the synovium lacks the typical changes seen in inflammatory arthritis.[unreadable] In cadherin-11 null mice, the inflammatory response in arthritis is attenuated and the synovium does not[unreadable] attach to or invade cartilage. The specific aims of this proposal are focused on elaborating the role of[unreadable] cadherin-11 in the production of matrix and synovlocyte proliferation (Aim 1), the capacity of FLS to[unreadable] migrate, attach to, and erode cartilage (Aim 2) and on their ability to participate in the inflammatory[unreadable] reaction and interact with macrophages in the synovium in in vitro models (Aim 3). Then, we will[unreadable] determine if cadherin-11 might serve as a new therapeutic target for inflammatory arthritis in vivo, reducing[unreadable] both the inflammatory reaction and cartilage damage alone or in combination with anti-TNF therapy (Aim[unreadable] 4). Together, these studies will reveal newly identified mechanisms relevant to understanding synovitis as[unreadable] well as point to potential therapeutic approaches that target FLS in inflammatory arthritis based on the[unreadable] expression and function of cadherin-11.